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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine.
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Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine.

机译:长期暴露于尼古丁后,受体脱敏可引发表面α4β2烟碱样受体的上调。

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摘要

It is hypothesized that desensitization of neuronal nicotinic acetylcholine receptors (nAChRs) induced by chronic exposure to nicotine initiates upregulation of nAChR number. To test this hypothesis directly, oocytes expressing alpha4beta2 receptors were chronically incubated (24-48 hr) in nicotine, and the resulting changes in specific [3H]nicotine binding to surface receptors on intact oocytes were compared with functional receptor desensitization. Four lines of evidence strongly support the hypothesis. (1) The half-maximal nicotine concentration necessary to produce desensitization (9.7 nM) was the same as that needed to induce upregulation (9.9 nM). (2) The concentration of [3H]nicotine for half-maximal binding to surface nAChRs on intact oocytes was also similar (11.1 nM), as predicted from cyclical desensitization models. (3) Functional desensitization of alpha3beta4 receptors required 10-fold higher nicotine concentrations, and this was mirrored by a 10-fold shift in concentrations necessary for upregulation. (4) Mutant alpha4beta2 receptors that do not recover fully from desensitization, but not wild-type channels, were upregulated after acute (1 hr) applications of nicotine. Interestingly, the nicotine concentration required for half-maximal binding of alpha4beta2 receptors in total cell membrane homogenates was 20-fold lower than that measured for surface nAChRs in intact oocytes. These data suggest that cell homogenate binding assays may not accurately reflect the in vivo desensitization affinity of surface nAChRs and may account for some of the previously reported differences in the efficacy of nicotine for inducing nAChR desensitization and upregulation.
机译:假设由于长期暴露于尼古丁引起的神经元烟碱乙酰胆碱受体(nAChRs)脱敏会引起nAChR数的上调。为了直接检验该假设,将表达α4beta2受体的卵母细胞在尼古丁中长期孵育(24-48小时),并将与完整卵母细胞表面受体特异性[3H]烟碱结合产生的变化与功能性受体脱敏进行比较。四行证据有力地支持了这一假设。 (1)产生脱敏作用所需的最大烟碱半浓度(9.7 nM)与诱导上调所需的最大浓度(9.9 nM)相同。 (2)[3H]烟碱与完整卵母细胞表面nAChRs的最大结合的一半浓度也相似(11.1 nM),这是根据周期性脱敏模型预测的。 (3)alpha3beta4受体的功能性脱敏需要高10倍的尼古丁浓度,这反映了上调所需浓度的10倍偏移。 (4)急性应用尼古丁后(1小时),不能从脱敏中完全恢复但不是野生型通道的突变体alpha4beta2受体被上调。有趣的是,总细胞膜匀浆中α4β2受体的半数最大结合所需的尼古丁浓度比完整卵母细胞表面nAChRs所测浓度低20倍。这些数据表明,细胞匀浆结合测定可能无法准确反映表面nAChRs的体内脱敏亲和力,并且可能解释了尼古丁在诱导nAChR脱敏和上调功效方面的某些先前报道的差异。

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